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EP3495361B1 - Sel et cristal de composé de diaza-benzofluorane - Google Patents

Sel et cristal de composé de diaza-benzofluorane Download PDF

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Publication number
EP3495361B1
EP3495361B1 EP17836407.1A EP17836407A EP3495361B1 EP 3495361 B1 EP3495361 B1 EP 3495361B1 EP 17836407 A EP17836407 A EP 17836407A EP 3495361 B1 EP3495361 B1 EP 3495361B1
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EP
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Prior art keywords
crystal form
compound
ray powder
powder diffraction
formula
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EP17836407.1A
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German (de)
English (en)
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EP3495361A4 (fr
EP3495361A1 (fr
Inventor
Qingqing LU
Shenyi SHI
Tiezhong Bai
Shujie Yuan
Zhengwu Li
Qiaofen HU
Yijie CAO
Jing Gao
Hui DING
Jinhua LI
Guanghai Xu
Zheng Wang
Xin Jin
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Harbin Pharmaceutical Group Co Ltd General Pharmaceutical Factory
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Harbin Pharmaceutical Group Co Ltd General Pharmaceutical Factory
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a hydrochloride salt, a citrate salt, a phosphate salt or a sulfate salt of compound 1, the crystal forms of the aforementioned salts, and a preparation method thereof.
  • the present invention also relates to their use in the preparation of a medicament for the treatment of cerebral apoplexy or epilepsy.
  • cerebral apoplexy has become the second leading cause of death, following ischemic heart disease; cerebral apoplexy is also very likely to lead to deformity and disability. It seriously affects the quality of life of patients and their family. Therefore, it is necessary to find a way to improve the health conditions of patients suffering from apoplexy and to restore their body function and ability to work, so that they can have a better quality of life and a good prognosis. This is beneficial to reduce the burden of not only individuals but also the whole society.
  • Vinpocetine which is represented by the formula B-I, is an indole alkaloid extracted from the lesser periwinkle plant. Vinpocetine is highly fat-soluble and can easily pass through the blood-brain barrier, so it is present in high concentration in brain tissues and have good efficacy. Vinpocetine is developed by Gedeon Richter Co., a Hungarian company, in 1978. It has a history of over 30 years in Europe. It is mainly used to relieve the symptoms caused by cerebral infarction sequelae, cerebral hemorrhage sequelae, and cerebral atherosclerosis, among others. Ever since vinpocetine first came into the market, it is regarded as a routine medicine to treat cardiovascular and cerebrovascular diseases.
  • vinpocetine can improve age-related memory impairment and the mental activities of healthy people.
  • vinpocetine can also act to treat confusion, attention-deficit disorder, irritability, visual and auditory disorders, and emotional fluctuation, among others.
  • the seizure occurrence rate is significantly reduced or there had been no incidence at all. It has a significant therapeutic effect on generalized tonic-clonic seizures.
  • Epilepsy is a chronic recurrent transient brain dysfunction syndrome and is characterized by an abnormal discharge of neurons in the brain, which leads to a risk of recurrent seizures.
  • Epilepsy is a common nervous system disease. Its prevalence is second only to cerebral apoplexy. The number of epilepsy patients in China is large, and the majority of patients are young adults and children under the age of 20. Its disability rate and mortality rate are also high, which has become a problem of concern for the whole society. Vinpocetine has various degrees of efficacy for over 67% of epilepsy patients, especially for generalized tonic-clonic seizures.
  • WO 2013/076646 discloses eburnamenine derivatives with a tetrazole substituent in position 14 of the core structure.
  • the present invention provides a hydrochloride salt, a citrate salt, a phosphate salt or a sulfate salt of compound 1.
  • the hydrochloride salt, the citrate salt, the phosphate salt or the sulfate salt of the aforementioned compound 1 is selected from:
  • the present invention also provides a crystal form A of a compound of formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at 2 ⁇ angles of 9.14 ⁇ 0.2 °, 10.43 ⁇ 0.2 °, 11.38 ⁇ 0.2°, 12.54 ⁇ 0.2°, 13.86 ⁇ 0.2°, 19.04 ⁇ 0.2°, 19.36 ⁇ 0.2°, 21.00 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of crystal form A of the compound of formula (I) is shown in Table-1.
  • the present invention also provides a crystal form B of the compound of formula (I), wherein an X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at 2 ⁇ angles of 9.17 ⁇ 0.2°, 11.75 ⁇ 0.2°, 12.16 ⁇ 0.2°, 12.67 ⁇ 0.2°, 15.14 ⁇ 0.2°, 17.81 ⁇ 0.2°, 20.54 ⁇ 0.2°, 22.34 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of crystal form B of the compound of formula (I) described above is shown in Table-2.
  • the present invention also provides a crystal form C of the compound of formula (II), wherein the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at 2 ⁇ angles of 14.04 ⁇ 0.2°, 16.28 ⁇ 0.2°, 16.70 ⁇ 0.2°, 17.73 ⁇ 0.2°, 18.18 ⁇ 0.2°, 20.29 ⁇ 0.2°, 23.40 ⁇ 0.2°, 25.95 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form C of the compound of formula (II) is shown in Table-3.
  • Table-3 analytical data of X-ray powder diffraction pattern of crystal form C of compound of formula (II) NO.
  • the present invention also provides a crystal form D of the compound of formula (III), wherein the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at 2 ⁇ angles of 4.47 ⁇ 0.2°, 9.80 ⁇ 0.2°, 10.67 ⁇ 0.2°, 13.05 ⁇ 0.2°, 16.30 ⁇ 0.2°, 16.80 ⁇ 0.2°, 17.65 ⁇ 0.2°, 17.82 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form D of the compound of formula (III) is shown in Table-4.
  • the present invention also provides a crystal form E of the compound of formula (IV), wherein the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at 2 ⁇ angles of 4.71 ⁇ 0.2°, 12.30 ⁇ 0.2°, 16.26 ⁇ 0.2°, 16.78 ⁇ 0.2°, 19.80 ⁇ 0.2°, 23.70 ⁇ 0.2°, 25.65 ⁇ 0.2°, 26.22 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form E of the compound of formula (IV) is shown in Table-5.
  • the present invention also provides a crystal form F of the compound of formula (IV), wherein the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at 2 ⁇ angles of 5.79 ⁇ 0.2°, 9.75 ⁇ 0.2°, 14.03 ⁇ 0.2°, 15.67 ⁇ 0.2°, 17.46 ⁇ 0.2°, 18.86 ⁇ 0.2°, 20.42 ⁇ 0.2°, 20.99 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form F of the compound of formula (IV) is shown in Table-6.
  • the present invention also provides a crystal form G of the compound of formula (V), wherein the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at 2 ⁇ angles of 4.59 ⁇ 0.2°, 12.24 ⁇ 0.2°, 15.93 ⁇ 0.2°, 16.66 ⁇ 0.2°, 18.46 ⁇ 0.2°, 19.72 ⁇ 0.2°, 22.10 ⁇ 0.2°, 23.56 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form G of the compound of formula (V) is shown in Table-7.
  • the present invention also provides a crystal form H of the compound of formula (V), wherein the X-ray powder diffraction pattern of the crystal form H has characteristic diffraction peaks at 2 ⁇ angles of 5.85 ⁇ 0.2°, 8.80 ⁇ 0.2°, 9.87 ⁇ 0.2°, 12.47 ⁇ 0.2°, 14.06 ⁇ 0.2°, 17.62 ⁇ 0.2°, 18.70 ⁇ 0.2°, 20.58 ⁇ 0.2°.
  • the analytical data of the X-ray powder diffraction pattern of the crystal form H of the compound of formula (V) is shown in Table-8.
  • the present invention also provides a method for preparing the aforementioned crystal forms, including contacting a free base with an acid, washing, and drying.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound described above or the crystal form(s) described above as an active ingredient and a pharmaceutically acceptable carrier.
  • the invention also provides a use of the compound described above in the manufacture of a medicament for the treatment of cerebral apoplexy or epilepsy.
  • the invention also provides a use of the crystal form described above in the preparation of a medicament for the treatment of cerebral apoplexy or epilepsy.
  • the invention also provides the use of the pharmaceutical composition described above in the preparation of a medicament for the treatment of cerebral apoplexy or epilepsy.
  • the crystal form A and crystal form B of the compound of formula (I), the crystal form C of the compound of formula (II), the crystal form D of the compound of formula (III), the crystal form E and crystal form F of the compound of formula (IV), the crystal form G and crystal form H of the compound of formula (V) provided in the present invention have stable properties, good solubility, and good hygroscopicity. These crystal forms have good prospects in pharmaceutical development.
  • each crystal form of the present invention is simple; no harsh conditions and highly toxic solvents are required.
  • the crystal forms obtained are of high purity and good yield; they are suitable for industrial scale-up.
  • the compounds of the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the embodiments described below, embodiments combining the embodiments described below with other synthetic methods, and equivalent alternatives known to those skilled in the art. Preferred embodiments include but are not limited to those embodiments of the present invention.
  • Solvents used in the present invention are commercially available.
  • the abbreviations used herein are as follows: aq is water; HATU is O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC is N-(3-Dimethylaminopropyl)-N' -ethylcarbodiimide; m-CPBA is 3-chloroperoxybenzoic acid; eq is equivalent; CDI is carbonyl diimidazole; DCM is dichloromethane; PE is petroleum ether; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; MeOH is methanol; CBz is benzyloxycarbonyl, which is an amine protecting group;
  • the solvents used in the present invention are commercially available. Commercially available compounds are described with catalog names provided by the suppliers.
  • the X-ray powder diffraction method is as follows:
  • Crystal form B was prepared using the preparation method of crystal form A, except that methanol was replaced with acetone to obtain crystal form B.
  • the assay measures PDE1A enzyme activity based on fluorescence polarization detection of AMP/GMP production.
  • the principle of the reaction is to replace the binding of AMP/GMP to its antibody by AlexaFluor 633 labeled AMP/GMP.
  • Enzyme substrate 1M cAMP or cGMP (Ca 2+ -calmodulin as a cofactor of PDE1A);
  • Enzymatic activity corresponding to the FP signal was retrieved in an AMP/GMP standard curve using DMSO as a control in an Excel table. The enzymatic activity was converted to nM product concentration. An analysis was performed using GraphPad Prism and IC 50 values were calculated.
  • Table 1 Table 1 IC 50 values measured by PDE1 detection Tested compound PDE1 Compound 1 1 uM ⁇ B ⁇ 20 uM

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  • Organic Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Claims (20)

  1. Un sel chlorhydrate, un sel citrate, un sel phosphate ou un sel sulfate du composé 1.
    Figure imgb0026
  2. Le sel chlorhydrate, le sel citrate, le sel phosphate ou le sel sulfate du composé 1 selon la revendication 1, choisis parmi:
    Figure imgb0027
    Figure imgb0028
    Figure imgb0029
    Figure imgb0030
  3. Forme cristalline A d'un composé de formule (I) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline A présente des pics de diffraction caractéristiques à 2θ angles de 9,14 ± 0,2 °, 10,43 ± 0,2 °, 11,38 ± 0,2 °, 12,54 ± 0,2 °, 13,86 ± 0,2 °, 19,04 ± 0,2 °, 19,36 ± 0,2 °, 21,00 ± 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  4. Forme cristalline A du composé de formule (I) selon la revendication 3, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 1; Tableau 1 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline A du composé de formule (I) NO. 2-Theta d(A) BG Height 1% Area 1% FWHM 1 6,939 12,7281 194 303 10,1 2387 9,8 0,132 2 9,145 9,6619 159 3007 100 24372 100 0,136 3 10,429 8,4755 166 1735 57,7 21585 88,6 0,209 4 11,375 7,7723 163 1175 39,1 8803 36,1 0,126 5 12,541 7,0524 143 702 23,3 5792 23,8 0,138 6 13,86 6,3841 140 1851 61,6 15060 61,8 0,136 7 14,667 6,0344 156 434 14,4 2968 12,2 0,115 8 17,091 5,1838 117 347 11,5 5241 21,5 0,253 9 18,121 4,8914 119 356 11,8 2772 11,4 0,131 10 19,044 4,6564 114 448 14,9 5014 20,6 0,188 11 19,364 4,58 111 672 22,3 7584 31,1 0,189 12 21 4,2269 118 791 26,3 16129 66,2 0,342 13 22,89 3,882 112 228 7,6 4152 17 0,305 14 23,857 3,7267 110 231 7,7 2565 10,5 0,186 15 25,041 3,5532 106 424 14,1 5190 21,3 0,205 16 25,931 3,4331 105 241 8 1966 8,1 0,137 17 27,431 3,2488 102 112 3,7 1649 6,8 0,247 18 27,822 3,204 96 242 8 3602 14,8 0,249 19 28,611 3,1173 94 207 6,9 1940 8 0,157 20 29,849 2,9908 101 108 3,6 1707 7 0,265 21 31,86 2,8065 102 129 4,3 1503 6,2 0.195
  5. Forme cristalline B d'un composé de formule (I) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline B présente des pics de diffraction caractéristiques à 2θ angles de 9,17 + 0,2 °, 11,75 + 0,2 °, 12,16 + 0,2 °, 12,67 + 0,2 °, 15,14 + 0,2 °, 17,81 + 0,2 °, 20,54 + 0,2 °, 22,34 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  6. La forme cristalline B du composé de formule (I) selon la revendication 5, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celle-ci sont présentées dans le tableau 2; Tableau-2 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline B du composé de formule (I) N° 2-Theta d(A) BG Height I% Area I% FWHM 1 9,169 9,6372 152 2286 100 14460 100 0,106 2 11,75 7,5254 129 373 16,3 2694 18,6 0,121 3 12,159 7,273 124 387 16,9 3007 20,8 0,13 4 12,671 6,9802 123 162 7,1 1021 7,1 0,106 5 15,135 5,8492 111 147 6,4 1564 10,8 0,178 6 17,604 5,0339 104 119 5,2 1433 9,9 0,202 7 17,808 4,9766 104 324 14,2 3418 23,6 0,177 8 18,786 4,7196 100 81 3,5 1440 10 0,298 9 20,542 4,32 92 206 9 2207 15,3 0,18 10 22,336 3,9769 94 172 7,5 1576 10,9 0,154 11 23,107 3,8459 95 115 5 854 5,9 0,124 12 24,546 3,6236 86 93 4,1 1096 7,6 0,198
  7. Forme cristalline C d'un composé de formule (II) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline C a des pics de diffraction caractéristiques à 2θ angles de 14,04 + 0,2 °, 16, 28 + 0,2 °, 16,70 + 0,2 °, 17,73 + 0,2 °, 18,18 + 0,2 °, 20,29 + 0,2 °, 23,40 + 0, 2 °, 25,95 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  8. Forme cristalline C du composé de formule (II) selon la revendication 7, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre sont présentées dans le tableau 3; Tableau 3 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline C du composé de formule (II) N° 2-Theta d(A) BG Height 1% Area 1% FWHM 1 11,906 7,4269 199 621 17,7 8896 17,7 0,24 2 12,541 7,0526 235 857 24,4 7933 15,8 0,155 3 12,993 6,8078 229 580 16,5 4706 9,4 0,136 4 13,485 6,5606 226 762 21,7 7061 14,1 0,155 5 14,038 6,3036 201 1934 55,1 20010 39,9 0,173 6 16,285 5,4383 210 3511 100 50131 100 0,239 7 16,698 5,3048 230 1528 43,5 35932 71,7 0,394 8 17,45 5,078 254 770 21,9 9366 18,7 0,204 9 17,727 4,9993 252 1356 38,6 15329 30,6 0,189 10 18,181 4,8753 220 2657 75,7 30925 61,7 0,195 11 19,855 4,4679 219 595 16,9 6908 13,8 0,195 12 20,288 4,3735 188 2536 72,2 30866 61,6 0,204 13 20,701 4,2871 219 693 19,7 7201 14,4 0,174 14 22,399 3,9658 182 930 26,5 11059 22,1 0,199 15 23,405 3,7976 239 2075 59,1 34231 68,3 0,277 16 24,175 3,6784 276 834 23,8 9352 18,7 0,188 17 24,451 3,6375 252 759 21,6 9899 19,7 0,219 18 25,948 3,431 177 1167 33,2 24521 48,9 0,352 19 26,797 3,3241 183 477 13,6 5767 11,5 0,203 20 28,533 3,1257 171 530 15,1 6737 13,4 0,213 21 36,777 2,4418 207 622 17,7 6964 13,9 0,188
  9. Forme cristalline D d'un composé de formule (III) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline D présente des pics de diffraction caractéristiques à 2θ angles de 4,47 + 0,2 °, 9,80 + 0,2 °, 10,67 + 0,2 °, 13,05 + 0,2 °, 16,30 + 0,2 °, 16,80 + 0,2 °, 17,65 + 0,2 °, 17,82 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  10. Forme cristalline D du composé de formule (III) selon la revendication 9, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 4; Tableau-4 - données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline D du composé de formule (III) N° 2-Theta d(A) BG Height 1 % Area 1% FWHM 1 4,473 19,7377 375 4844 100 45331 100 0,157 2 9,8 9,0181 176 1638 33,8 11819 26,1 0,121 3 10,666 8,2874 169 3717 76,7 30915 68,2 0,139 4 12,476 7,0888 184 1251 25,8 9047 20 0,121 5 13,051 6,778 177 1602 33,1 10873 24 0,114 6 13,427 6,589 166 1310 27 10573 23,3 0,135 7 16,13 5,4903 160 1106 22,8 37399 82,5 0,567 8 16,305 5,4318 160 2131 44 25688 56,7 0,202 9 16,799 5,2733 188 1641 33,9 15451 34,1 0,158 10 17,648 5,0213 181 2686 55,5 37888 83,6 0,236 11 17,82 4,9733 183 1431 29,5 43578 96,1 0,51 12 18,868 4,6993 175 646 13,3 7760 17,1 0,201 13 19,536 4,5402 208 533 11 4140 9,1 0,13 14 20,034 4,4284 167 740 15,3 12737 28,1 0,289 15 21,118 4,2035 165 712 14,7 6251 13,8 0,147 16 21,414 4,146 158 1336 27,6 12539 27,7 0,157 17 23,308 3,8132 225 1207 24,9 9801 21,6 0,136 18 24,271 3,6641 219 606 12,5 7376 16,3 0,204 19 25,91 3,4358 169 404 8,3 6287 13,9 0,261 20 27,31 3,2629 189 400 8,3 5345 11,8 0,224
  11. Forme cristalline E d'un composé de formule (IV) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline E présente des pics de diffraction caractéristiques à 2θ angles de 4,71 + 0,2 °, 12,30 + 0,2 °, 16,26 + 0,2 °, 16,78 + 0,2 °, 19,80 + 0,2 °, 23,70 + 0,2 °, 25,65 + 0,2 °, 26,22 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  12. Forme cristalline E du composé de formule (IV) selon la revendication 11, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 5; Tableau 5 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline E du composé de formule (IV) N° 2-Theta d(A) BG Height 1% Area 1% FWHM 1 4,707 18,7589 309 3145 71,7 31611 82,2 0,168 2 11,631 7,6017 214 423 9,6 4278 11,1 0,17 3 12,302 7,1886 179 4388 100 38447 100 0,147 4 13,857 6,3854 163 337 7,7 3636 9,5 0,181 5 16,265 5,445 195 1333 30,4 23473 61,1 0,295 6 16,776 5,2802 224 2172 49,5 18674 48,6 0,144 7 17,547 5,05 229 1011 23 7789 20,3 0,129 8 18,02 4,9185 237 817 18,6 6923 18 0,142 9 18,554 4,7782 232 1272 29 16970 44,1 0,224 10 19,185 4,6225 221 473 10,8 5261 13,7 0,186 11 19,798 4,4807 205 2435 55,5 21568 56,1 0,148 12 21,257 4,1763 190 594 13,5 6130 15,9 0,173 13 21,726 4,0871 199 500 11,4 4069 10,6 0,136 14 22,854 3,888 166 721 16,4 11013 28,6 0,256 15 23,287 3,8166 181 891 20,3 14107 36,7 0,265 16 23,701 3,7509 230 1289 29,4 18099 47,1 0,235 17 24,626 3,612 203 552 12,6 7936 20,6 0,241 18 25,652 3,4699 211 1044 23,8 26708 69,5 0,429 19 26,223 3,3957 199 1116 25,4 17573 45,7 0,264 20 28,254 3,1559 191 491 11,2 11951 31,1 0,408 21 35,473 2,5285 141 225 5,1 3009 7,8 0,224 22 36,42 2,4649 122 312 7,1 4645 12,1 0,25
  13. Forme cristalline F d'un composé de formule (IV) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline F présente des pics de diffraction caractéristiques à 2θ angles de 5,79 + 0,2 °, 9,75 + 0,2 °, 14,03 + 0,2 °, 15,67 + 0,2 °, 17,46 + 0,2 °, 18,86 + 0,2 °, 20,42 + 0,2 °, 20,99 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  14. Forme cristalline F du composé de formule (IV) selon la revendication 13, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 6; Tableau 6 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline F du composé de formule (IV) N° 2-Theta d(A) BG Height 1% Area 1% FWHM 1 5,786 15,2623 306 516 47,9 5073 28,7 0,165 2 7,426 11,8947 203 379 35,2 3988 22,6 0,176 3 8,703 10,1521 176 397 36,9 3247 18,4 0,137 4 9,75 9,0638 164 1016 94,3 9956 56,4 0,164 5 10,933 8,0861 170 338 31,4 2723 15,4 0,135 6 11,425 7,7387 177 354 32,9 3564 20,2 0,169 7 12,331 7,1718 163 481 44,7 4126 23,4 0,144 8 14,029 6,3074 151 735 68,2 7028 39,8 0,16 9 14,346 6,169 151 321 29,8 3591 20,3 0,188 10 15,666 5,652 156 760 70,6 9522 53,9 0,21 11 16,117 5,4947 162 322 29,9 4586 26 0,239 12 17,005 5,2098 182 192 17,8 2181 12,3 0,19 13 17,461 5,0748 203 706 65,6 6622 37,5 0,157 14 18,545 4,7804 207 363 33,7 6555 37,1 0,303 15 18,862 4,7007 204 1077 100 17667 100 0,275 16 19,705 4,5016 208 310 28,8 2593 14,7 0,14 17 20,419 4,3457 213 927 86,1 9467 53,6 0,171 18 20,991 4,2286 183 708 65,7 8791 49,8 0,208 19 22,767 3,9026 178 468 43,5 5533 31,3 0,198 20 23,337 3,8087 174 182 16,9 2200 12,5 0,203 21 24,048 3,6975 164 275 25,5 5361 30,3 0,327 22 25,411 3,5023 146 235 21,8 2471 14 0,176 23 27,184 3,2777 147 355 33 5433 30,8 0,257
  15. Forme cristalline G d'un composé de formule (V) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline G présente des pics de diffraction caractéristiques à 2θ angles de 4,59 + 0,2 °, 12,24 + 0,2 °, 15,93 + 0,2 °, 16,66 + 0,2 °, 18,46 + 0,2 °, 19,72 + 0,2 °, 22,10 + 0,2 °, 23,56 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  16. Forme cristalline G du composé de formule (V) selon la revendication 15, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 7; Tableau 7 - Données analytiques du diagramme de diffraction des rayons X sur poudre de forme cristalline G du composé de formule (V) N° 2-Theta d(A) BG Height 1% Area 1% FWHM 1 4,59 19,236 3 385 1667 38,4 15045 38,5 0,151 2 9,304 9,4971 191 598 13,8 5628 14,4 0,158 3 11,435 7,7317 235 684 15,7 4328 11,1 0,106 4 12,241 7,2246 202 4343 100 39033 100 0,151 5 15,929 5,5592 241 1991 45,8 21713 55,6 0,183 6 16,662 5,3164 306 838 19,3 5317 13,6 0,106 7 17,463 5,0742 251 484 11,1 3508 9 0,121 8 17,883 4,956 291 785 18,1 6452 16,5 0,138 9 18,455 4,8035 233 2706 62,3 32968 84,5 0,204 10 19,065 4,6513 240 267 6,1 2947 7,6 0,185 11 19,716 4,4991 260 804 18,5 7452 19,1 0,155 12 20,25 4,3817 248 324 7,5 4879 12,5 0,252 13 21,667 4,0982 251 304 7 1984 5,1 0,109 14 22,103 4,0183 237 923 21,3 6305 16,2 0,115 15 22,758 3,9042 254 570 13,1 6434 16,5 0,189 16 23,564 3,7724 230 1019 23,5 16018 41 0,263 17 24,587 3,6177 222 680 15,7 6927 17,7 0,171 18 25,378 3,5067 272 495 11,4 7444 19,1 0,252 19 25,868 3,4413 223 1128 26 17421 44,6 0,259 20 26,107 3,4105 234 408 9,4 10890 27,9 0,447 21 27,673 3,2209 211 116 2,7 2389 6,1 0,345 22 28,057 3,1776 213 433 10 6604 16,9 0,256 23 29,068 3,0694 189 288 6,6 4102 10,5 0,239 24 29,499 3,0255 176 140 3,2 3873 9,9 0,464
  17. Forme cristalline H d'un composé de formule (V) selon la revendication 2, dans laquelle un diagramme de diffraction des rayons X sur poudre de la forme cristalline H présente des pics de diffraction caractéristiques à 2θ angles de 5,85 + 0,2 °, 8,80 + 0,2 °, 9,87 + 0,2 °, 12,47 + 0,2 °, 14,06 + 0,2 °, 17,62 + 0,2 °, 18,70 + 0,2 °, 20,58 + 0,2 °; un procédé de diffraction des rayons X sur poudre pour obtenir le diagramme de diffraction des rayons X sur poudre est le suivant: cible: Cu: K-Alpha; longueur d'onde λ = 1,54179Å.
  18. Forme cristalline H du composé de formule (V) selon la revendication 17, dans laquelle les données analytiques du diagramme de diffraction des rayons X sur poudre de celui-ci sont présentées dans le tableau 8; Tableau 8 - Données analytiques du diagramme de diffraction des rayons X sur poudre de la forme cristalline H du composé de formule (V) N° 2-Theta d(A) BG Height 1% Area 1% FWHM 1 5,848 15,1009 258 680 70,3 7041 64,8 0,174 2 7,543 11,711 178 308 31,9 3618 33,3 0,197 3 8,803 10,0372 169 718 74,3 5934 54,6 0,139 4 9,869 8,9545 164 877 90,7 10726 98,8 0,205 5 10,968 8,0599 164 295 30,5 2465 22,7 0,14 6 11,688 7,5649 162 203 21 2735 25,2 0,226 7 12,471 7,0921 160 379 39,2 5453 50,2 0,241 8 13,144 6,73 156 286 29,6 2751 25,3 0,161 9 14,065 6,2915 146 337 34,9 2894 26,7 0,144 10 15,212 5,8196 161 284 29,4 2527 23,3 0,149 11 17,324 5,1146 144 132 13,7 3403 31,3 0,432 12 17,618 5,0298 150 967 100 10859 100 0,188 13 18,703 4,7404 161 396 41 8250 76 0,349 14 19,06 4,6524 159 336 34,7 5882 54,2 0,293 15 20,577 4,3128 169 381 39,4 7041 64,8 0,31 16 24,326 3,6559 129 142 14,7 1825 16,8 0,215
  19. Procédé de préparation de la forme cristalline selon l'une quelconque des revendications 3 à 18, comprenant la mise en contact d'une base libre avec un acide, le lavage et le séchage.
  20. Composition comprenant le composé selon la revendication 1 ou la forme cristalline selon l'une quelconque des revendications 3 à 7 à utiliser dans un procédé de traitement de l'apoplexie cérébrale ou de l'épilepsie.
EP17836407.1A 2016-08-04 2017-08-03 Sel et cristal de composé de diaza-benzofluorane Not-in-force EP3495361B1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268245A2 (fr) * 1986-11-17 1988-05-25 Sanwa Kagaku Kenkyusho Co., Ltd. Procédé de préparation de dérivés d'oxime de l'éburnamenine
WO2013076646A1 (fr) * 2011-11-22 2013-05-30 Richter Gedeon Nyrt. Nouveau dérivé du diaza-benzofluoranthène en tant que médicament
WO2016124129A1 (fr) * 2015-02-04 2016-08-11 南京明德新药研发股份有限公司 Composés diaza-benzofluoranthrène

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU166474B (fr) * 1971-11-03 1975-03-28
DE3479423D1 (en) * 1984-02-29 1989-09-21 Covex Sa Citrate of vinpocetine, and process for its preparation
ES2097703B1 (es) * 1995-04-12 1997-12-01 Decox S L Una nueva composicion estimulante de la actividad cerebral basada en alcaloides de nucleo de eburnamenina, y sus metodos de preparacion.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268245A2 (fr) * 1986-11-17 1988-05-25 Sanwa Kagaku Kenkyusho Co., Ltd. Procédé de préparation de dérivés d'oxime de l'éburnamenine
WO2013076646A1 (fr) * 2011-11-22 2013-05-30 Richter Gedeon Nyrt. Nouveau dérivé du diaza-benzofluoranthène en tant que médicament
WO2016124129A1 (fr) * 2015-02-04 2016-08-11 南京明德新药研发股份有限公司 Composés diaza-benzofluoranthrène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ÁDÁM VAS ET AL: "Eburnamine derivatives and the brain", MEDICINAL RESEARCH REVIEWS, vol. 25, no. 6, 1 November 2005 (2005-11-01), US, pages 737 - 757, XP055577477, ISSN: 0198-6325, DOI: 10.1002/med.20043 *

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EP3495361A4 (fr) 2019-06-12
BR112019002216A2 (pt) 2019-05-14
RU2019105922A3 (fr) 2020-09-04
AU2017306606A1 (en) 2019-03-21
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ES2837573T3 (es) 2021-06-30
UA122731C2 (uk) 2020-12-28
RU2762189C2 (ru) 2021-12-16
AU2017306606A8 (en) 2019-12-05
WO2018024225A1 (fr) 2018-02-08
JP6977236B2 (ja) 2021-12-08
AU2017306606B2 (en) 2020-04-30
IL264651A (fr) 2019-04-30
PH12019500248A1 (en) 2019-10-21
RU2019105922A (ru) 2020-09-04
KR20190035854A (ko) 2019-04-03
ZA201901155B (en) 2020-10-28
CN109563090A (zh) 2019-04-02
EP3495361A1 (fr) 2019-06-12
JP2019523306A (ja) 2019-08-22

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